Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma

Mitsuteru Natsuizaka, Kelly A. Whelan, Shingo Kagawa, Koji Tanaka, Veronique Giroux, Prasanna M. Chandramouleeswaran, Apple Long, Varun Sahu, Douglas S. Darling, Jianwen Que, Yizeng Yang, Jonathan P. Katz, E. Paul Wileyto, Devraj Basu, Yoshiaki Kita, Shoji Natsugoe, Seiji Naganuma, Andres J. Klein-Szanto, J. Alan Diehl, Adam J. Bass, Kwok-Kin Wong (), Anil K. Rustgi and Hiroshi Nakagawa ()
Additional contact information
Mitsuteru Natsuizaka: University of Pennsylvania
Kelly A. Whelan: University of Pennsylvania
Shingo Kagawa: University of Pennsylvania
Koji Tanaka: University of Pennsylvania
Veronique Giroux: University of Pennsylvania
Prasanna M. Chandramouleeswaran: University of Pennsylvania
Apple Long: University of Pennsylvania
Varun Sahu: Abramson Cancer Center
Douglas S. Darling: University of Louisville
Jianwen Que: Columbia University
Yizeng Yang: University of Pennsylvania
Jonathan P. Katz: University of Pennsylvania
E. Paul Wileyto: Abramson Cancer Center
Devraj Basu: Abramson Cancer Center
Yoshiaki Kita: Kagoshima University Graduate School of Medical and Dental Sciences
Shoji Natsugoe: Kagoshima University Graduate School of Medical and Dental Sciences
Seiji Naganuma: Kochi Medical School
Andres J. Klein-Szanto: Fox Chase Cancer Center
J. Alan Diehl: Medical University of South Carolina
Adam J. Bass: Harvard Medical School
Kwok-Kin Wong: Harvard Medical School
Anil K. Rustgi: University of Pennsylvania Perelman School of Medicine
Hiroshi Nakagawa: University of Pennsylvania Perelman School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial–mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01500-9

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DOI: 10.1038/s41467-017-01500-9

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